Prostate cancer is the most frequently diagnosed non-dermatological malignancy in North American men. While screening and early detection have reduced mortality, there is still no curative treatment for advanced disease. As such all patients that develop castration-resistant tumors will ultimately die from their disease. Therefore developing an effective therapy for advanced prostate cancer represents an important unmet clinical need. By targeting two important oncogenic pathways we have identified a combination therapy that kills castration-resistant prostate cancer. Notably, while many (failed) targeted therapies have been shown to slow prostate cancer growth, this drug combination actually causes frank tumor regression in vivo in several models. The goal of this project is to deconstruct the mechanism by which these agents function, use this insight to identify the optimal drugs/targets, and validate the therapeutic effects of these agents in patient-derived xenograft (PDX) models. This will be accomplished through cellular, epigenetic, and genomic approaches and by conducting additional preclinical studies in vivo. These studies will not only provide invaluable preclinical data to guide the development of a clinical trial, but will uncover mechanisms that kill castration- resistant prostate cancer, which may ultimately lead to the development of additional therapeutic strategies.